It is known that reduced coenzyme Q10 can be prepared by producing coenzyme Q10 in the conventional manner, for example by synthesis, fermentation, or extraction from natural products, and concentrating a reduced coenzyme Q10-containing eluate fraction resulting from chromatography (JP-A-10-109933). On that occasion, as described in the above-cited publication, the chromatographic concentration may be carried out after reduction of oxidized coenzyme Q10 contained in the reduced coenzyme Q10 with a conventional reducing agent such as sodium borohydride or sodium dithionite (sodium hyposulfite), or reduced coenzyme Q10 may be prepared by reacting the reducing agent mentioned above with an existing highly pure grade of coenzyme Q10.
JP-A-57-70834 discloses an example in which reduced coenzyme Q10 was synthesized by dissolving coenzyme Q10 in hexane and adding an aqueous solution of sodium hydrosulfite (sodium hyposulfite) in an amount of twice the weight of coenzyme Q10 to the solution, followed by stirring.
However, the conventional methods require operations such as extraction of the generated reduced coenzyme Q10 with an organic solvent and concentration, thus the process time becomes inevitably long, and also require an expensive production apparatus and large capacity.
Moreover, when trying to distilling off a solvent from an organic phase containing reduced coenzyme Q10, reduced coenzyme Q10 precipitates in the form of semi-solid or solid during the operation, which leads to troublesome conditions such as increase of stirring load and stirring failure, and as a result, the solvent removal tends to be incomplete. Generally, this phenomenon tends to become marked when the purity of reduced coenzyme Q10 is high.
Such characteristic of reduced coenzyme Q10 causes a problem not only in isolating reduced coenzyme Q10 but also in preparing a solution or slurry of reduced coenzyme Q10 prepared by substituting the solvent of the organic phase mentioned above with another solvent, such as the case of carrying out crystallization. The solvent substitution requires such a complicated operation as repeating a solvent removal process with supplementing a solvent, thus, problems are caused on the commercial scale such as workability, cost efficiency and quality, as described below.
In the case of substituting a solvent having a high-boiling point into a solvent having a low-boiling point or the case that solvents to be used each other form an azeotrope, solvent substitution becomes an extremely inefficient process which consumes much solvent and a lot of time. Additionally, unfavorable components or impurities, which coexists in the solvent to be supplemented (e.g. high-boiling point components or hardly volatile components) accumulate in the solution in a high concentration. For example, as in a case of substitution of a heptane solution having a high boiling point to a tetrahydrofuran solution having a low boiling point, the solvent substitution becomes an extremely inefficient, and there is a possibility that stabilizers such as 2,6-di-tert-butyl-4-hydroxytoluene (BHT), which coexists in tetrahydrofuran, accumulate in the solution in a high concentration more than necessity.
Moreover, reduced coenzyme Q10 is readily oxidized into oxidized coenzyme Q10 by molecular oxygen. On a commercial production scale, complete oxygen elimination is very difficult to achieve and, furthermore, fairly long periods of time are required for individual operations, unlike laboratory scale production, so that residual oxygen exerts a great adverse effect. The oxidation in question is directly connected with such yield and quality problems as the formation of hardly eliminable oxidized coenzyme Q10 and immixture into the product. For obtaining highly pure reduced coenzyme Q10, it is preferable to shorten the operation time for such as concentration and solvent substitution in view of adequate protection of the reduced form from the oxidation mentioned above.
Therefore, it has been desired a method for directly and easily obtaining reduced coenzyme Q10 without requiring additional operations such as extraction with an organic solvent and concentration, etc., and/or a method for distilling off an organic solvent from the organic phase containing reduced coenzyme Q10 in a convenient manner and in a short time, without causing stirring failure.